Colorectal Cancer
Conditions
Brief summary
This open-label, single arm, multicenter study evaluated the resection rate in participants with colorectal cancer and previously untreated unresectable liver-only metastases after adding bevacizumab to 5-FU based doublet chemotherapy in the neoadjuvant setting. Participants receive standard 5-FU based chemotherapy plus Avastin bevacizumab 5 milligrams per kilogram (mg/kg) every 2 weeks for a maximum of 12 cycles combined pre- and postoperatively, unless they experienced progressive disease or unacceptable toxicity.
Interventions
DRUG5-FU based doublet chemotherapy
Standard 5-FU based doublet chemotherapy. Protocol did not specify any particular chemotherapy regimen. The choice of 5-FU based doublet chemotherapy was as per standard of practice and the dosage of 5-FU based doublet chemotherapy was as per product labels.
DRUGbevacizumab
5 mg/kg every 2 weeks, up to 12 cycles pre- and postoperatively
Sponsors
Hoffmann-La Roche
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Adult Chinese participants, 18-75 years of age * Histologically confirmed adenocarcinoma in colon or rectum with primary lesion surgically removed * Previously untreated unresectable liver-only metastases * Liver lesions determined to be unresectable by multidisciplinary team (MDT, consisting of experienced hepatic surgeons, medical oncologist and radiologist). * No previous treatment against liver metastases, including chemotherapy, surgery, radiotherapy, Transarterial chemoembolisation therapy (TACE) and target therapy * Adequate hematological, renal and hepatic function * Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 * Life expectancy greater than (\>) 3 months
Exclusion criteria
* The relapse has occurred within 6 months of completion of the adjuvant treatment * Expected impossible to achieve complete resection (R0 resection) and/or gain 30% residual liver volume even with responsive neoadjuvant therapy * Participant cannot tolerate the surgery * Other malignancies in the past 5 years, except for curatively treated basal cell carcinoma of the skin and/or in situ carcinoma of the cervix * Any extrahepatic metastases and/or recurrence of the primary tumor * Any residual toxicity from previous chemotherapy (except alopecia) of National Cancer Institute Common Toxicity Criteria (NCI CTC) v.4.0 grade 2 * Hypertension crisis or encephalopathy * Pregnant or lactating women * Clinically significant cardiovascular disease * Evidence of bleeding diathesis or coagulopathy * Current or recent (within 10 days of study drug initiation) use of full dose of aspirin, clopidrogel or warfarin * History or evidence of Central Nervous System (CNS) disease (for example, primary brain tumor, seizures not controlled with standard medical therapy, any brain metastases, or history of stroke)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Complete Resection (R0 Resection) | At time of surgery (up to 28 weeks), 48 hours post-surgery and 4 and 12 weeks after surgery (up to 40 weeks) | R0 resection was defined as complete resection confirmed by pathology after pre-operative chemotherapy plus bevacizumab. Participants with R0 resections based on assessments performed at time of surgery, 48 hours post-surgery and 4 and 12 weeks after surgery were reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Objective Response | Screening until disease progression or death until data cutoff on 12 May 2016 (up to approximately 3.5 years overall) | Objective response rate was defined as the percentage of participants who achieved either Partial Response (PR) or Complete Response (CR) per Response Evaluation Criteria In Solid Tumors (RECIST) version (v) 1.1. This is defined as the best response recorded from the start of trial treatment until disease progression (or death). CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis less than \[\<\] 10 mm). No new lesions. PR was defined as greater than or equal to \[≥\] 30 percent (%) decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions. |
| Number of Participants With Disease Progression or Relapse or Death | Screening until disease progression or death until data cutoff on 12 May 2016 (up to approximately 3.5 years overall) | According to RECIST v1.1 Progressive Disease is defined as a 20 % or greater increase in the sum of the longest diameter of measured lesions (target lesions) taking as reference the smallest lesion diameter recorded since the treatment started or appearance of one or more new non-target lesions. |
| Progression Free Survival (PFS) | Screening until disease progression or death until data cutoff on 12 May 2016 (up to approximately 3.5 years overall) | Progressive Disease is defined as a 20% or greater increase in the sum of the longest diameter of measured lesions (target lesions) taking as reference the smallest lesion diameter recorded since the treatment started or appearance of one or more new non-target lesions. PFS was defined as the time from initiation of study treatment to disease progression, as determined by the investigator using RECIST v1.1 criterion, or relapse after resection of liver metastases or death from any cause. Kaplan-Meier curves were used to display PFS. |
| Percentage of Participants Achieving Incomplete Tumor Resection (R1 Resection) | At time of surgery (up to 28 weeks), 48 hours post-surgery and 4 and 12 weeks after surgery (up to 40 weeks) | R1 resection was defined as achievement of incomplete tumor resection with microscopic involvement of a margin after pre-operative chemotherapy plus bevacizumab, as confirmed by pathology. Participants with R1 resections based on assessments performed at time of surgery, 48 hours post-surgery and 4 and 12 weeks after surgery were reported. |
| Number of Participants With Disease Relapse or Death | Screening until disease progression or death until data cutoff on 12 May 2016 (up to approximately 3.5 years overall) | — |
| Disease Free Survival (DFS) | Complete resection date up to disease relapse or death until data cutoff on 12 May 2016 (up to approximately 3.5 years) | Disease Free Survival (DFS) was defined as the time from complete resection of liver metastases to disease relapse or death, for participants who achieve complete resection after pre-operative treatment with standard 5-FU based doublet regimen plus bevacizumab. |
| Percent Probability Of Being Alive and Disease Free at Months 3, 6, 9, and 12 | Months 3, 6, 9, and 12 | — |
| Percent Probability (PP) of Being Alive and Progression Free at Months 3, 6, 9, 12, 15, and 18 | Months 3, 6, 9, 12, 15, and 18 | Progressive Disease is defined as a 20% or greater increase in the sum of the longest diameter of measured lesions (target lesions) taking as reference the smallest lesion diameter recorded since the treatment started or appearance of one or more new non-target lesions. PFS was defined as the time from initiation of study treatment to disease progression, as determined by the investigator using RECIST v1.1 criterion, or relapse after resection of liver metastases or death from any cause. The probability was estimated by Kaplan Meier curve analysis. |
Countries
China
Participant flow
Pre-assignment details
Protocol did not specify any particular 5-Flurouracil (5-FU) based doublet chemotherapy regimen. The choice of 5-FU based doublet chemotherapy was as per standard of practice and the dosage of 5-FU based doublet chemotherapy was as per product labels.
Participants by arm
| Arm | Count |
|---|---|
| Bevacizumab Participants received standard 5-FU based chemotherapy plus bevacizumab 5 mg/kg intravenous infusion every two week cycle for a maximum of 12 cycles unless they experienced progressive disease, unacceptable toxicities or participant refusal. | 50 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Investigator Decision | 5 |
| Overall Study | Lost to Follow-up | 4 |
| Overall Study | Progressive Disease | 8 |
| Overall Study | Protocol Violation | 2 |
| Overall Study | Unspecified Reason | 1 |
| Overall Study | Withdrawal by Subject | 18 |
Baseline characteristics
| Characteristic | Bevacizumab |
|---|---|
| Age, Continuous | 56.1 years STANDARD_DEVIATION 9.71 |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 26 / 50 |
| serious Total, serious adverse events | 4 / 50 |
Outcome results
Primary
Percentage of Participants Achieving Complete Resection (R0 Resection)
R0 resection was defined as complete resection confirmed by pathology after pre-operative chemotherapy plus bevacizumab. Participants with R0 resections based on assessments performed at time of surgery, 48 hours post-surgery and 4 and 12 weeks after surgery were reported.
Time frame: At time of surgery (up to 28 weeks), 48 hours post-surgery and 4 and 12 weeks after surgery (up to 40 weeks)
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab | Percentage of Participants Achieving Complete Resection (R0 Resection) | 30.0 percentage of participants |
Secondary
Disease Free Survival (DFS)
Disease Free Survival (DFS) was defined as the time from complete resection of liver metastases to disease relapse or death, for participants who achieve complete resection after pre-operative treatment with standard 5-FU based doublet regimen plus bevacizumab.
Time frame: Complete resection date up to disease relapse or death until data cutoff on 12 May 2016 (up to approximately 3.5 years)
Population: ITT population; Here, number of participants analyzed = participants who underwent study specified surgery. Participants who underwent surgery but did not achieve complete resection were censored.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab | Disease Free Survival (DFS) | 8.48 months |
Secondary
Number of Participants With Disease Progression or Relapse or Death
According to RECIST v1.1 Progressive Disease is defined as a 20 % or greater increase in the sum of the longest diameter of measured lesions (target lesions) taking as reference the smallest lesion diameter recorded since the treatment started or appearance of one or more new non-target lesions.
Time frame: Screening until disease progression or death until data cutoff on 12 May 2016 (up to approximately 3.5 years overall)
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab | Number of Participants With Disease Progression or Relapse or Death | 28 participants |
Secondary
Number of Participants With Disease Relapse or Death
Time frame: Screening until disease progression or death until data cutoff on 12 May 2016 (up to approximately 3.5 years overall)
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab | Number of Participants With Disease Relapse or Death | 20 participants |
Secondary
Percentage of Participants Achieving Incomplete Tumor Resection (R1 Resection)
R1 resection was defined as achievement of incomplete tumor resection with microscopic involvement of a margin after pre-operative chemotherapy plus bevacizumab, as confirmed by pathology. Participants with R1 resections based on assessments performed at time of surgery, 48 hours post-surgery and 4 and 12 weeks after surgery were reported.
Time frame: At time of surgery (up to 28 weeks), 48 hours post-surgery and 4 and 12 weeks after surgery (up to 40 weeks)
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab | Percentage of Participants Achieving Incomplete Tumor Resection (R1 Resection) | 0.0 percentage of participants |
Secondary
Percentage of Participants Achieving Objective Response
Objective response rate was defined as the percentage of participants who achieved either Partial Response (PR) or Complete Response (CR) per Response Evaluation Criteria In Solid Tumors (RECIST) version (v) 1.1. This is defined as the best response recorded from the start of trial treatment until disease progression (or death). CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis less than \[\<\] 10 mm). No new lesions. PR was defined as greater than or equal to \[≥\] 30 percent (%) decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions.
Time frame: Screening until disease progression or death until data cutoff on 12 May 2016 (up to approximately 3.5 years overall)
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab | Percentage of Participants Achieving Objective Response | 30.0 percentage of participants |
Secondary
Percent Probability Of Being Alive and Disease Free at Months 3, 6, 9, and 12
Time frame: Months 3, 6, 9, and 12
Population: ITT population
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Bevacizumab | Percent Probability Of Being Alive and Disease Free at Months 3, 6, 9, and 12 | 3 Months | 80.0 PP of being alive and disease free |
| Bevacizumab | Percent Probability Of Being Alive and Disease Free at Months 3, 6, 9, and 12 | 6 Months | 70.0 PP of being alive and disease free |
| Bevacizumab | Percent Probability Of Being Alive and Disease Free at Months 3, 6, 9, and 12 | 9 Months | 40.0 PP of being alive and disease free |
| Bevacizumab | Percent Probability Of Being Alive and Disease Free at Months 3, 6, 9, and 12 | 12 Months | 20.0 PP of being alive and disease free |
Secondary
Percent Probability (PP) of Being Alive and Progression Free at Months 3, 6, 9, 12, 15, and 18
Progressive Disease is defined as a 20% or greater increase in the sum of the longest diameter of measured lesions (target lesions) taking as reference the smallest lesion diameter recorded since the treatment started or appearance of one or more new non-target lesions. PFS was defined as the time from initiation of study treatment to disease progression, as determined by the investigator using RECIST v1.1 criterion, or relapse after resection of liver metastases or death from any cause. The probability was estimated by Kaplan Meier curve analysis.
Time frame: Months 3, 6, 9, 12, 15, and 18
Population: ITT population; Number of participants analyzed equals (=) number of participants who had surgery.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bevacizumab | Percent Probability (PP) of Being Alive and Progression Free at Months 3, 6, 9, 12, 15, and 18 | 3 Months | 97.7 PP of being alive and progression free |
| Bevacizumab | Percent Probability (PP) of Being Alive and Progression Free at Months 3, 6, 9, 12, 15, and 18 | 6 Months | 76.4 PP of being alive and progression free |
| Bevacizumab | Percent Probability (PP) of Being Alive and Progression Free at Months 3, 6, 9, 12, 15, and 18 | 9 Months | 59.5 PP of being alive and progression free |
| Bevacizumab | Percent Probability (PP) of Being Alive and Progression Free at Months 3, 6, 9, 12, 15, and 18 | 12 Months | 51.5 PP of being alive and progression free |
| Bevacizumab | Percent Probability (PP) of Being Alive and Progression Free at Months 3, 6, 9, 12, 15, and 18 | 15 Months | 30.0 PP of being alive and progression free |
| Bevacizumab | Percent Probability (PP) of Being Alive and Progression Free at Months 3, 6, 9, 12, 15, and 18 | 18 Months | 21.4 PP of being alive and progression free |
Secondary
Progression Free Survival (PFS)
Progressive Disease is defined as a 20% or greater increase in the sum of the longest diameter of measured lesions (target lesions) taking as reference the smallest lesion diameter recorded since the treatment started or appearance of one or more new non-target lesions. PFS was defined as the time from initiation of study treatment to disease progression, as determined by the investigator using RECIST v1.1 criterion, or relapse after resection of liver metastases or death from any cause. Kaplan-Meier curves were used to display PFS.
Time frame: Screening until disease progression or death until data cutoff on 12 May 2016 (up to approximately 3.5 years overall)
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab | Progression Free Survival (PFS) | 12.06 months |